The long-term objective of this project is to determine the mechanisms that cause obesity in individuals eating a diet high in fat. Specifically, this project will address signals generated from the gastrointestinal (GI) tract that regulate food intake. The central hypothesis in this project is that consumption of a high-fat diet impairs satiety signaling from the GI tract so that meal size is increased chronicity and over time obesity develops. Based on this hypothesis we predict that rats fed HF diets will have decreased mechanisms using three important GI peptides that suppress food intake: Cholecystokinin (CCK), Gastrin-releasing peptide (GRP), and Apolipoprotein A-IV (apo A-IV). The specific aims of this project are to determine: 1) whether HF diets decrease the anorectic response to satiety peptides, and whether this occurs at the level of the gut or CNS, 2) whether HF diets impair the initiation of satiety by altering the synthesis of secretion of satiety peptides, and 3) the mechanism by which HF diets impair the secretion of apo A-IV. Rats that have been maintained on high-fat (HF), low fat (LF), and normal pelleted rat chow diets in the Animal Core of the Program Project will be used in all studies. Release of CCK, GRP, and apo A-IV will be measured in intestinal lymph, and peptide and mRNA content determined in segments of intestine to assess the effects of diet on synthesis and secretion of satiety factors. Finally, we will study apo A-IV release from the intact GI tract and from segments of gut isolated from the nutrient system to determine whether HF diets inhibit lipid stimulated apo A-IV secretion through enteral or systemic processes. It is anticipated that these studies will advance the understanding of food intake regulation, help to explain the pathogenesis of obesity and provide a model for new treatment strategies to be developed.